Parkinson's disease (PD) is a debilitating neurodegenerative disorder of unknown etiology that results in the loss of dopaminergic neurons within the nigrostriatal pathway and clinically manifests as bradykinesia, resting tremor, and rigidity. Individuals suffering from PD receive variable symptomatic relief from early pharmacologic therapy in the form of the dopamine precursor, levadopa (L-DOPA). Upon entry into the CNS, L-DOPA is decarboxylated into dopamine by the critical enzyme aromatic-amino-dopa-decarboxylase (AADC). Long-term utilization of L-DOPA and progressive disease leads to side effects including dyskinesias and a narrowing of the therapeutic window. Gene transfer technologies may provide modalities by which the therapeutic window of L-DOPA therapy can be widened and side effects minimized. Adeno-associated virus (rAAV)- and lentivirus (rHIV)-based vectors have shown promise in the delivery and long-term expression of therapeutic genes within the mammalian CNS. Our hypothesis is as follows: Delivery of the AADC gene to the striata of parkinsonian monkeys via rAAV or rHIV vectors will result in extended L-DOPA efficacy and reduced occurrence of drug-induced dyskinesias. To test this hypothesis, the following experiments are to be conducted in a standardized parkinsonian non-human primate model: (i) evaluate the clinical efficacy of rAAV- and rHIV-based AADC gene transfer modalifies in combination with L-DOPA administration; (ii) evaluate these approaches in their potential to alleviate L-DOPA-induced dyskinesias; and (iii) correlate clinical efficacy with increased conversion of L-DOPA to dopamine using biochemical assessments. These experiments will provide a unique opportunity for evaluation of a combined gene therapeutic/pharmacologic approach using two promising gene transfer vectors to alleviate the potentially disabling and frequently dose-limiting complications of L-DOPA therapy.